Useful substances have often poor solubility in water in the fields of pharmaceutical products, veterinary pharmaceutical products, quasi-drugs, cosmetic products, food products, agricultural chemicals, and the like. This restricts the use of useful substances. In general, as methods for increasing the solubility of poorly-soluble drugs or increasing the dissolution rate thereof, a method involving mechanical microparticulation, a method in which such a poorly-soluble drug is included with cyclodextrin or the like, a method in which the solubility of such a poorly-soluble drug is increased using a surfactant or a solubilizer, and the like have been adopted.
There are various types of methods for administering pharmaceutical products, such as oral administration, intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, transnasal administration, and pulmonary administration. In the case of oral administration, for example, in order that an orally administered drug effectively acts on a living body, first of all, the drug must be disintegrated, dissolved and absorbed into the body. When the drug used has extremely low solubility in water, the blood concentration of the drug becomes low, and as a result, an entire amount of the drug is not absorbed and a portion of the drug is eliminated from the body in the undissolved form. Thus, expected drug effects may not be obtained in some cases. In addition, in the case of cutaneous administration, a drug cannot be sufficiently absorbed transdermally when poorly-soluble powder is merely incorporated into an ointment or a patch base such as a poultice. Thus, such a poorly-soluble drug in a dissolved state must be mixed into the base. In many cases, such a poorly-soluble drug must be mixed into alcohols at a high concentration, and thus, it is unfavorable in terms of skin safety. Moreover, in the case of intravenous administration, when a drug to be administered has low solubility, it is difficult to administer the drug by intravenous administration. In all of these administration methods, the solubility of a drug to be administered is associated with retardation of the time at which an effective blood concentration is achieved or a decrease in biological availability. Hence, the solubility of a drug has great influence on the effects of the drug.
Furthermore, in the case of a whitening ingredient used in cosmetic products, its effect is expressed as a result of penetration into the skin. Accordingly, it is important to improve the transdermal absorbency of the whitening ingredient. Thus, it is necessary that the solubility of a poorly-soluble substance be increased and that the transdermal absorbency thereof be improved.
Further, in the case of an agricultural chemical that is poorly soluble in water, it is slowly dissolved, and sufficient drug effects cannot be achieved in some cases. Accordingly, in the case of a granular agricultural chemical containing a poorly water-soluble ingredient as an active ingredient, promotion of dissolution of the active ingredient is important. As insecticidal ingredients, there are many poorly water-soluble drugs. When a pharmaceutical preparation such as a liquid preparation is produced, a kerosene-type solvent is often used because of usability such as odor or stimulation, low toxicity, high safety due to a high flash point, as well as compatibility with insecticidal ingredients. The solubility of such insecticidal ingredients is generally low. On the other hand, these ingredients have high solubility in solvents such as acetone, toluene, xylene and chloroform. However, these solvents have a low flash point, high toxicity, and strong odor. Thus, they are generally impractical.
Hence, the improvement of the solubility of a poorly-soluble drug is extremely important in the fields of pharmaceutical products, veterinary pharmaceutical products, quasi-drugs, cosmetic products, food products, agricultural chemicals, and the like.
Under the aforementioned circumstances, a large number of methods have been proposed, such as a method in which the surface area of a poorly-soluble drug is increased by microparticulation, a method in which such a poorly-soluble drug is included in cyclodextrin or the like, a method in which such a poorly-soluble drug is converted into an amorphous form, a method in which pH is adjusted, and a method in which the solubility of such a poorly-soluble drug is increased using a solubilizer or an organic solvent. Moreover, at present, nano-level microparticulation technology has attracted attention. This is a micellisation technology or a technology using surfactants. The technology using surfactants is a most commonly used technique.
For example, the following methods have been disclosed: a method, which comprises mixing a poorly-soluble drug with sugar or sugar alcohol, and then subjecting the mixture to high-speed stirring grinding or impact grinding to obtain ultrafine particles, so as to increase the surface area of drug particles and to enhance the dissolution rate of the drug due to water solubility and dispersibility of the sugars (see Patent Document 1); a method, which comprises dissolving or suspending a poorly-soluble drug and a polymeric carrier such as hydroxylpropyl methyl cellulose or polyvinyl pyrrolidone in a mixed solution of water and an organic solvent such as alcohol, and then grinding and drying it by pulse combustion drying to obtain spherical fine particles of the poorly-soluble drug and the polymeric carrier, so as to increase the surface area of the drug particles and to thereby enhance the dissolution rate of the drug (see Patent Document 2); a method in which a poorly-soluble drug is included in cyclodextrin, a derivative thereof or the like to improve the solubility of the drug (see Patent Document 3); a method in which a poorly-soluble drug is grinded together with crystalline cellulose to convert it into an amorphous form, so as to increase the solubility of the drug (see Patent Document 4); a method, which comprises melting a poorly-soluble acidic drug or a salt thereof, and then mixing the resultant with a basic magnesium-containing compound to convert the acidic drug or the salt thereof to an amorphous form, so as to increase the solubility of the drug (see Patent Document 5); a method in which a fatty acid ester of 2-ethyl-2-butyl-1,3-propanediol is used as a solubilizer for a poorly-soluble drug (see Patent Document 6); a method, which comprises dissolving glycyrrhizinic acid and a poorly-soluble drug in an organic solvent or the like, and then distilling away the solvent, so as to increase the solubility of the drug and the dissolution rate thereof (Patent Document 7); a method of improving the solubility of a pharmaceutical preparation, which comprises dissolving a poorly-soluble drug having micelle formation ability in water to form a micelle, and then fixing the micellar structure formed in the poorly-soluble drug, using a compound for fixing such a micellar structure (Patent Document 8); and a method, which comprises dissolving a poorly water-soluble drug and one or two or more types of nonionic surfactants in a solvent, then mixing an inorganic carrier into the resultant, so that the poorly water-soluble drug and the nonionic surfactant(s) are adsorbed on the carrier, and then removing the solvent (see Patent Document 9).
The method involving the microparticulation of a drug is a most commonly used technique of improving the solubility of the drug. In reality, such a microparticulation range is up to approximately several micrometers, and thus, microparticulation does not contribute to an increase in the solubility so much. On the contrary, there may be a case in which the cohesiveness or adhesiveness of a drug is increased by microparticulation, a drug is consolidated, or the dissolution rate is decreased. In addition, in the method in which a drug is included in cyclodextrin or the like, a freeze-drying method or the like is generally used. This method includes a long production time and a large number of steps, and thus, it cannot be said that this method is advantageous in terms of industrialization. Moreover, in order to include a drug in cyclodextrin or the like, it is generally necessary to use cyclodextrin in the same amount as that of the drug. Hence, as the amount of such an additive increases, the amount of the drug also increases. Furthermore, in the case of the method in which a drug is converted into an amorphous form, such an amorphous form is inherently an unstable state, and it is easily converted to a crystalline state that is a stable form by an external stimulation such as light, heat or humidity, or with time. Hence, it is difficult to maintain an amorphous form. Further, in the case of the method of increasing the solubility of a poorly-soluble drug using a solubilizer, an organic solvent is generally used. Thus, there is a possibility that such an organic solvent remains in a pharmaceutical preparation, and it causes safety problem. Since a large amount of organic solvent should be recovered safely from the viewpoint of environmental preservation, it leads to high production costs, and this method is also problematic in terms of the health maintenance and safety of workers. Still further, in the case of the method using a surfactant, the amount of a surfactant that can be used in a pharmaceutical preparation is generally approximately several hundreds of milligrams, taking into consideration the toxicity of the surfactant. However, this amount is not sufficient for increasing solubility. On the other hand, if a sufficient amount of surfactant is used to increase solubility, such a large amount of surfactant causes great damage on the intestinal mucosa (see Non-Patent Document 1).